Recently, Hebei Provincial Market Supervision Administration organized and formulated the "Technical Specifications for Clinical Operation of Cellular Immunotherapy." This document specifies relevant terms and definitions, basic requirements, risk plans, implementation plan formulation, implementation and operation, treatment of side effects, patient follow-up, etc. This document is applicable to medical institutions and cell preparation institutions that implement cellular immunotherapy. The specification document will be implemented on February 21, 2021.

Today, the Stem Cell Official Account released the full text of this specification document for reference by counterparts in the cell therapy industry.

Technical specification for clinical operation of cellular immunotherapy
 
 
Foreword
 
This document was drafted in accordance with the rules given in GB/T1.1-2020 "Guidelines for Standardization Work Part 1: Structure and Drafting Rules of Standardization Documents".
Please note that some of the contents of this document may involve patents. The issuing agency of this document is not responsible for identifying these patents. This document was proposed by Hebei Provincial Health Commission.
This document was drafted by: Nongfuyu Pharmaceutical Hebei Co., Ltd., Hebei Provincial People's Hospital, Hebei Institute of Cell Biotechnology. The main drafters of this document: Cai Jianhui, Li Qingxia, Du Pingping, Zhang Mengya, Deng Xinna, Gao Fei, Zhou Ye, Cai Ziqi.
This document is issued for the first time.

 
Introduction
 
In recent years, cellular immunotherapy has gradually been applied to the clinic, but the current domestic and provincial clinical operating technical specifications for cellular immunotherapy are still blank. In order to adapt to the development needs of the cellular immunotherapy industry, strengthen the quality control and safety management of the clinical application of cellular immunotherapy, standardize the clinical operation technical process and risk control of cellular immunotherapy, ensure the rights and safety of patients, and promote international and domestic cooperation in the same industry. For communication, it is necessary to formulate technical specifications for the clinical operation of cellular immunotherapy.
 
1 Scope
 
This document specifies relevant terms and definitions, basic requirements, risk plans, implementation plan formulation, implementation and operation, treatment of side effects, patient follow-up, etc.
This document is applicable to medical institutions and cell preparation institutions that implement cellular immunotherapy.
 
2 Normative references
 
There are no normative references in this document.
 
3 Terms and definitions
 
The following terms and definitions apply to this document.
3.1
Cell preparation institution cellpreparationinstitution
Enterprises, institutions or laboratories with cell preparation professionals, GMP-like cell culture rooms, professional facilities and equipment conditions and qualifications.
3.2
Medical institution medicalinstitution
Hospitals or departments that have the personnel, venues, facilities and equipment required for cellular immunotherapy and meet the national qualifications.
3.3
Peripheral blood mononuclear cell; PBMC
Mononuclear cells in the blood mainly include lymphocytes, monocytes, macrophages, dendritic cells, NK cells and a small number of other types of cells.
3.4
RawmaterialT cell rawmaterialT cell
T lymphocytes derived from autologous PBMC, separated and/or sorted to prepare effector cells; or derived from allogeneic or tissue
Compatible antigen matching and/or gene editing are used to prepare T lymphocytes for effector cells.
3.5
Effectorcell
Lymphocytes that are obtained through in vitro processing, preparation, culture and expansion, and capable of non-specific or specific recognition and killing of target cells.
3.6
Chimeric antigen receptor T cells chimericantigenreceptorTcells; CAR-T
Modified by genetic engineering, it can express imported signals containing antigen recognition fragments, T cell receptor activation molecules, costimulatory signals, etc.
Molecular CAR gene effector T cells.
3.7
T cell receptor chimeric type T cell T cell receptor chimeric type Tcells; TCR-T

 
Modified by genetic engineering, it can express the introduced MHC-limited effector T cells containing TCR genes that can recognize specific MHC antigen complexes.
3.8
Tumor infiltrating T lymphocytes tumorinfiltrating lymphocytes; TIL
Specific tumor-infiltrating T lymphocytes isolated and expanded from tumor tissues.
3.9
Cytotoxic Tlymphocytes; CTL
Tumor-specific cytotoxic T lymphocytes activated by mature DC cells loaded with tumor antigens.
3.10
Therapeutic DCvaccine (therapeutic DC vaccine)
Immature DC cells (ImmatureDCcells) are mature DC cells (MatureDCcells) prepared by culturing, expanding and carrying tumor antigens.
3.11
Natural killer cells naturalkillercells; NK
NK cells are MHC non-limiting, non-specific natural killer cells that are cultured and differentiated with the participation of cytokines such as IL-2, IL-12, IFN-α and LR.
3.12
Dendriticcell-cytokine-induced killercells: DC-CIKCD3 monoclonal antibody and a variety of cytokine-induced non-specific killer cells co-cultured with DC cells to obtain a group of heterogeneous cells. Note: For non-specific cellular immunotherapy. However, if it is co-cultured with antigen-loaded DC cells, the DC-CIK cells obtained have partial specific killing.
Injury characteristics.
3.13
Transduction
The process of introducing exogenous genetic material (DNA or RNA) into cells for stable expression with the help of viral or non-viral vectors.
3.14
Gene editing
Use genetic engineering technology to knock out specific genomes of cell chromosomes, or perform a genetic modification process of random or site-specific insertion of the target genome.
3.15
Finalcellproduct
Refers to the final cell culture or harvest made from raw cells through the entire process of in vitro preparation, culture and expansion.
3.16
Label
Marks, notes, or barcodes pasted or attached to objects to distinguish different objects.
3.17
GMP-like cell culture room GMP-likecelllaboratory
A cell culture room with specialized cell culture facilities and equipment with a space of more than 10,000 grades and some 100 grades.
3.18
KPS score Kamofskyscore
Refers to the patient's physical function status score.
Note: Generally, a score of 80 or more is considered to be non-dependent, 50 to 70 is considered to be semi-dependent, and a score of less than 50 is considered to be dependent.
3.19
ECOG score Zubrod-ECOG-WHOscore

 
Refers to the patient's physical status and treatment tolerance score.
Note: Generally, 0~3 points can tolerate treatment, but 4 points or more cannot tolerate treatment.
3.20
Lymphocytedeletionchemotherapy lymphocytedeletionchemotherapy
Refers to the use of specific chemotherapeutic drugs to treat patients with chemotherapy for the purpose of non-myeloid lymphocyte deletion.
3.21
Preconditioning
Refers to the pre-treatment of patients with specific drugs for the purpose of enhancing the therapeutic effect or preventing toxic and side effects.
 
4 Basic requirements
 
4.1 Personnel requirements
 
4.1.1 The medical institution (hereinafter referred to as the institution) should be equipped with a team of medical staff suitable for its scale. The physician team should include at least three physicians, and at least one physician has senior professional title qualifications (associate senior and above); the nursing team should include at least four nurses, and at least one nurse has intermediate qualifications or above.
4.1.2 All members of the medical care team should have received professional training in cellular immunotherapy, and at least one or more physicians or nurses should have a professional training certificate in cellular immunotherapy.
4.1.3 The institution should have a team of experts for emergency treatment of cellular immunotherapy. The team members should at least include experts in cardiovascular medicine, respiratory medicine, hematology, and ICU and have expert qualifications (associate senior and above), and have multidisciplinary emergency response. Early warning mechanism for handling.
4.2 Institutional qualifications
 
4.2.1 Institutions that implement cellular immunotherapy should have Class III A or equivalent hospital qualifications.
4.2.2 Institutions should have the professional conditions for multidisciplinary emergency treatment required for cellular immunotherapy.
4.2.3 The institution should have an ethics committee, and each cellular immunotherapy technology or product must be ethically identified before it can be implemented in the institution.
4.3 Site, facilities, equipment
 
4.3.1 The institution shall have the premises and facilities that meet the requirements of cellular immunotherapy, including wards and facilities, medical units and facilities, nursing units and facilities, etc.
4.3.2 The organization should have the equipment conditions for emergency treatment, including oxygen inhalation equipment, sputum suction equipment, ECG monitoring equipment, auxiliary breathing equipment, etc.
4.3.3 The organization should have the necessary venues, facilities and equipment for the rescue of critical illnesses.
 
5 Risk plan
 
5.1 The institution shall formulate corresponding risk plans for the implementation of each cellular immunotherapy technology or product.
5.2 The risk plan shall formulate corresponding treatment measures on the basis of comprehensive consideration of the various risks that may occur during the entire implementation process of the implemented technology or product, so as to ensure the safety of patients during the entire implementation process.
 
6 Formulation of the implementation plan
 
6.1 The institution shall formulate a corresponding implementation plan for each cellular immunotherapy technology or product to be implemented to ensure the safety and effectiveness of each treatment.

 
6.2 The formulation of the implementation plan should fully take into account the characteristics of the technology or product implemented, and comply with relevant regulations and guidelines such as the "Administrative Measures for Clinical Research and Transformation Application of Somatic Cell Therapy", "Technical Guidelines for Research and Evaluation of Cell Therapy Products".
 
7 Implementation and operation
 
7.1 Patient evaluation
 
7.1.1 The evaluation of patients with autologous cellular immunotherapy includes evaluation before peripheral blood PBMC collection and evaluation before reinfusion therapy:
a) The content of patient assessment before PBMC collection includes but is not limited to:
1) No active infectious diseases;
2) Cardiopulmonary function, liver function, and kidney function are basically normal;
3) KPS score >50 or ECOG score below 3;
4) White blood cell (WBC) count>4.0×109/L, lymphocyte count>2.0×109/L, hemoglobin (HGB)>90g/L, platelet (PLT) count>100×109/L; bilirubin ≤1.5 Times the upper limit of normal value, alanine aminotransferase (ALT) ≤ 2 times the upper limit of normal value, and aspartate aminotransferase (AST) ≤ 2 times the upper limit of normal value;
5) Infectious disease test: hepatitis B surface antigen, hepatitis B E antigen, antibody, hepatitis B core antibody, hepatitis C (HCV) antibody, AIDS (HIV) antibody, syphilis antibody are all negative. Those who are positive for any of them need to be specially marked and notify the cell preparation agency to prepare cells in an independent preparation space to prevent cross-contamination.
b) The content of patient evaluation before reinfusion treatment includes but not limited to:
1) No infectious disease;
2) Cardiopulmonary function, liver function, and kidney function are basically normal;
3) KPS score>50 or ECOG score below 3 points.
7.1.2 The evaluation of allogeneic cell immunotherapy includes evaluation of T cell donors and evaluation of patients before reinfusion:
a) The evaluation of raw material T cell donors should strictly follow the "Technical Guidelines for Cell Therapy Product Research and Evaluation" and "CAR-T Cell Therapy Product Quality Control Testing Research and Non-clinical Research Considerations" and other relevant regulations;
b) The content of patient assessment before reinfusion treatment is the same as above.
 
7.2 Collection and transportation of peripheral blood PBMC
 
7.2.1 The blood collection department approved by the health administration department should use an automatic blood component separator to set up a mononuclear cell separation program to collect peripheral PBMC-enriched blood; or use qualified medical equipment to collect patient peripheral blood through a vein.
7.2.2 The collected peripheral blood PBMC should be treated with anticoagulation.
7.2.3 The transfer of peripheral blood PBMC should be delivered to a cell preparation facility equipped with a GMP-like cell culture room within 3 hours at 4°C.
 
7.3 Preparation and transportation of effector cell preparations
 
7.3.1 The preparation of effector cell preparations should be completed in a cell preparation facility equipped with a GMP-like cell culture room.
7.3.2 The preparation process of different effector cell preparations must strictly follow the "Technical Guidelines for the Research and Evaluation of Cell Therapy Products (Trial)", "Immune Cell Preparation Quality Management Standards", and "CAR-T Cell Preparation Quality Management Standards" (Draft for Solicitation of Comments)" and other norms or guidelines are implemented.
7.3.3 Each batch of effector cell preparations shall undergo strict period inspection and release inspection for quality control. The quality control indicators shall include but not limited to: cell number, cell viability, cell phenotype, functional molecule expression, cytokine secretion Function, in vitro killing function, pH value, osmotic pressure, endotoxin, rapid sterility test, bacterial and fungal culture test, mycoplasma culture test, harmful residue test, and each batch of cell preparation samples should be frozen for traceability.
7.3.4 The final product of effector cell preparations can adopt two methods: fresh cell preparations or frozen cell preparations.

 
7.3.5 The transport of effector cell preparations shall adopt the following methods:
a) Fresh effector cell preparations should be transported to the ward at 4°C. The transfer to reinfusion treatment generally does not exceed 12 hours;
b) The effector cell preparations cryopreserved in liquid nitrogen should be transported in a gas-phase liquid nitrogen tank to avoid the risk of liquid nitrogen overflow or contamination of the frozen storage bag rupture.
 
7.4 Cell handover
 
7.4.1 After the cells are transported to the ward, the full-time medical staff and transport personnel need to check, inspect and hand over the cell preparations together.
7.4.2 Check items include, but are not limited to: the patient's name, gender, hospitalization number, cell batch number, production date, release inspection result, signature of the inspector and other information shown in the cell packaging bag (bottle) mark. The inspection items include but are not limited to: whether the cell packaging bag (bottle) is damaged, leaking, leaking, and whether the content is abnormal.
7.4.3 If any problems are found, immediately contact the cell preparation institution for re-check; if there are any uncertain factors, immediately return to the cell preparation institution and discard it.
7.4.4 When transferring cell preparations from multiple patients, special care should be taken to avoid confusion.
7.4.5 Fresh cell preparations should be temporarily stored at 4°C during the time period from the completion of handover to reinfusion treatment, and the room temperature should not exceed 30 minutes; cryopreserved cell preparations should be placed as soon as possible during the time period from the completion of handover to reinfusion treatment The liquid nitrogen tank should be frozen and stored at room temperature for no more than 30 minutes after re-thawing.
7.5 Lymphocyte-depleting chemotherapy preconditioning
 
Commonly used regimen is cyclophosphamide 300mg/m2～400mg/m2 intravenous infusion once a day, on the 1st to 2nd day; fludarabine 20mg/m2～25mg/m2 intravenous infusion 1 time per day, on the 1st to 4th day day. The purpose is to reduce the level of immunosuppressive cells and factors in the tumor microenvironment through the deletion of non-myeloid lymphocytes to improve clinical efficacy. Should be 2-7 days after pretreatment